MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis

Abstract

Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3ʹUTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)-/- mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2-/- mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.

Sphingolipids in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Ceramide Turnover

“…Regarding their effect in the hepatocyte, both an upregulated A-SMase expression and ceramide content have been related to cell death [89] through activation of death receptors as fatty acid synthase (FAS) and TNFR1 [95]. The induction of necrosis in CCl 4 -treated mice, a fibrosis model widely studied [13,96], has been also correlated with an increase of ceramide content both in serum and liver [97]. Correlated with TNF, previously cited to deplete GSH levels in the cell during NASH, hepatocytes have been described to be more susceptible for cell death in that context [98,99].…”

miR‐193a/b‐3p relieves hepatic fibrosis and restrains proliferation and activation of hepatic stellate cells

“…A research by Ma et al reported that miR‐214 promoted the development of liver fibrosis via inducing the activation of HSCs . In addition, miR‐873‐5p has been demonstrated to be a marker for liver fibrosis and regulate the early stages of liver fibrosis . MiR‐351 has been confirmed to promote liver fibrosis via targeting the vitamin D receptor, and miR‐351 inhibition is recognized as a therapeutic intervention for fibrotic diseases .…”

Integration of high‑throughput data of microRNA and mRNA expression profiles reveals novel insights into the mechanism of liver fibrosis

“…A number of studies have reported that miRNAs are involved in the regulation of liver fibrosis (38–40). let-7i, miR-342-3p, miR-188-5p and miR-34a are upregulated in CCl 4 -treated fibrotic livers compared with control samples, while miR-202, miR-378b and miR-378d are downregulated (41).…”